1. Technical Field
The present invention relates to antibodies cross-reactive to human and mouse c-Met and uses thereof.
2. Description of the Related Art
Various grow factors, such as a hepatocyte growth factor (HGF), an epidermal growth factor (EGF), a vascular endothelial growth factor (VEGF), and a fibroblast growth factor (FGF), cross react with receptor tyrosine kinases (RTKs) on cellular surfaces to induce critical cell physiological regulation, such as, cell growth, differentiation, neovascularization, and tissue repair, as well as development. These growth factors and receptors, when deregulated in a physiological aspect, such as mutation, overexpression, and promotion of self activation, cause abnormal cell growth or differentiation, thereby initiating and promoting the development of cancers Lemmon M A & Schlessinger J, Cell. 141:1117-1134, 2010).
The met proto-oncogene (MET; c-Met) has been known as a proto-oncogene expressing hepatocyte growth factor (HGF)/scatter factor (SF) receptors (Dean M et al., Nature. 318:385-388, 1985, Gherardi et al., Nat. Rev. Cancer. 12:89-103, 2012), and cross-reacts with HGF, which is the only known ligand thereof, to induce mesenchymal-epithelial transition (MET) and promote cancer cell growth, invasion, and metastasis. Since c-Met is involved in mechanisms of development, metastasis, invasion, neovascularization, and the like, regardless of the ligand HGF, in the development procedure of several tumors, c-Met has been considered as an effective anti-cancer target. Based on this background, research on c-Met inhibitors, such as chemical drugs and monoclonal antibodies are being actively conducted (Comoglio P M et al., Nat. Rev. Drug. Discov. 7:504-516, 2008).
The development of antagonistic antibodies against the anticancer target c-Met is a representative strategy for anti-cancer therapy by c-Met inhibition. Anti-c-Met antibodies have been reported to inhibit the interaction between the ligand HGF and c-Met or decompose and inactivate c-Met. For example, the one-armed antagonistic antibody ‘OA-5D5’ developed as an anti-c-Met antibody is an agonist, and was developed as an antibody that is modified not to have an adverse effect, such as inducing c-Met dimerization (Martens T et al., Clin. Cancer Res. 15:6144-6152, 2006), and ‘DN30’ was developed to induce the inhibition of tumor formation by inducing the inactivation of c-Met itself to lose the function thereof (Petrelli A et al., PNAS. 103:5090-5095, 2006). However, the one-armed antagonistic antibody showed a slightly tumor suppressing effect when used alone, but a significant therapy effect when used together with chemotherapy, and the c-Met inactivating antibody was verified to be low competitive with ligand and show partial effects as an agonist. Therefore, the development of therapeutic antibodies that suppress functions of human c-Met has been continuously required.
In the development of antibodies against the anticancer target, in vitro efficacy evaluation as well as in vivo preclinical efficacy evaluation using mouse tumor models is needed. In particular, at the time of the evaluation of efficacy using mouse tumor models, therapeutic efficacies of corresponding antibodies are primarily determined through preclinical experiment results, such as the ability to reduce the confirmable tumor size and an increase in the survival period. Here, the used mouse tumor model is prepared by the injection of human-derived cancer cells overexpressing the anticancer target. In fact, it is highly possible that the correlation between preclinical and clinical results is low due to the interference of human tumor cells as well as mouse-derived cells mixed with the human tumor cells in the tumor microenvironment in the mouse at the time of the verification of antibody therapeutic effects (Talmadge J E et al., Am. J. Pathol. 170:793-804, 2007). Therefore, the combinatorial treatment of not only antibodies inhibiting only the human-derived anticancer target but also antibodies inhibiting the mouse-derived anticancer target or its ligand, or antibodies specific to human/mouse heterogeneous anticancer target can show more accurate preclinical therapy results. For example, it has been reported that, as for anti-Dll4 (delta like ligand 4) antibodies inhibiting intra-tumoral angiogenesis, when the mouse tumor model was treated with the combinatorial treatment of not only antibody against human Dll4 but also antibody against mouse Dll4, the tumor sizes were significantly reduced (Hoey T et al., Cell Stem Cell. 5:168-177, 2009). Also, as for antibodies targeting vascular endothelial growth factor receptor 2 (VEGFR-2) or vascular endothelial growth factor (VEGF), antibodies cross-reactive to human/mouse heterogeneous anticancer target exhibited high tumor inhibitory effect in the mouse tumor model, which demonstrated the necessity of the development of cross-reactive antibodies (Huang J et al., Cytotechnology. 62:61-71, 2010; Liang W-C et al., J. Biol. Chem. 281:951-961, 2006).
As described above, anti-c-Met antibodies suppressing only the function of c-Met do not have mouse c-Met receptor inhibitory action with regard to autocrine/paracrine action of human- or mouse-derived hepatocyte growth factor, and thus effects thereof are difficult to evaluate at the time of preclinical efficacy evaluation in the mouse tumor model. Since human c-Met (P08581, UniProtKB/Swiss-Prot) consists of 1,390 amino acids and mouse c-Met (P16056, UniProtKB/Swiss-Prot) consists of 1,379 amino acids, they have high amino acid sequence similarity of at least 89% therebetween (Chan A M L et al., Oncogene. 2:593-599, 1988). Also, as for the ligand hepatocyte growth factor (HGF), human HGF and mouse HGF have very high sequence similarity of at least 90% (Tashiro K et al., PNAS. 87:3200-3204, 1990). In addition, the representative sites of action of the ligand and the receptor are also the sema domain. Therefore, the possibility of development and applicability of cross-reactive antibodies is high. Therefore, it is necessary to develop antibodies cross-reactive to human/mouse c-Met, which suppress the cancer-specific ligand-receptor action in the tumoral microenvironment with regard to human/mouse c-Met, thereby confirming effective preclinical research results in the mouse tumor model.
Throughout the entire specification, many papers and patent documents are referenced and their citations are represented. The disclosures of cited papers and patent documents are entirely incorporated by reference into the present specification, and the level of the technical field within which the present invention falls and details of the present invention are explained more clearly.